Dextrorotatory Research Articles

Pharmacodynamic differences between racemic ibuprofen and dexibuprofen in murine preclinical study

Non-steroidal anti-inflammatory drugs (NSAIDs) are among the best therapeutic options to treat pain, but their use is restricted by their adverse effects. In this study, the pharmacological profile of ibuprofen and dexibuprofen was evaluated using the murine acetic acid writhing test, and the participation of naltrexone, naltrindole, nor-binaltorphimine, L-NAME, risperidone, and tropisetron in the antinociceptive efficacy. Antinociception was assessed by dose–response curves to ibuprofen and dexibuprofen before and after the i.p. administration of 1,0 mg/kg of naltrexone, or naltrindole, or norbinaltorphimine, or 5 mg/kg of L-NAME, 0,5 mg/kg of risperidone, or tropisetron in the murine assay. Results are presented as means ± SEM and differences calculated by one-way ANOVA followed by Tukey's post-test. Ibuprofen and dexibuprofen produced a dose-dependent antinociceptive effect with different potency. After pretreatment of mice with naltrexone, naltrindole, nor-binaltorphimine, L-NAME, risperidone, or tropisetron, a significant increase in ibuprofen efficacy was obtained, however, no effect on dexibuprofen activity was obtained. Data demonstrate that ibuprofen and dexibuprofen induce effective antinociception in the acetic acid writhing test, either directly, through COX inhibition, or indirectly, through the modulatory effects of opioid or serotonin, or nitric oxide receptors. These actions are complex since the effects depending on the chemical structure of the NSAID. Thus, a racemic compound (ibuprofen) induces a significant increase in nociceptive efficacy. However, they have no effect on the dextrorotatory enantiomer (dexibuprofen).

Structural and clinical characterization of CYP11B2 inhibition by dexfadrostat phosphate

Aldosterone synthase (CYP11B2) represents a promising drug target because its genetic dysregulation is causally associated with cardiovascular disease, its autonomous activity leads to primary aldosteronism, and its deficiency leads to salt wasting syndromes. The serendipitous discovery that the dextro-rotatory stereoisomer of the racemic aromatase (CYP19A1) inhibitor CGS16949A mediates potent CYP11B2 inhibition led to the purification and clinical development of dexfadrostat phosphate. To characterize the pharmacophore of dexfadrostat phosphate, structure-based enzyme coordination with CYP11B2, CYP11B1 and CYP19A1 was combined with steroid turnover upon in vitro and clinical treatment. Dexfadrostat, but not its 5S-enantiomer (5S-fadrozole), precisely coordinates with the catalytic heme moiety in the space of the CYP11B2 substrate binding pocket forming a tight and stable complex. Conversely, neither rigid nor flexible docking led to a plausible coordination geometry for dexfadrostat in steroid 11β-hydroxylase (CYP11B1 – orthologue to CYP11B2) or in CYP19A1. The inhibitory preference of dexfadrostat was confirmed in vitro using an adrenal cortex-derived cell line. Dexfadrostat phosphate treatment of healthy subjects in the context of a clinical phase 1 study led to a dose-dependent decrease in urinary aldosterone secretion, accompanied by an increase in urinary corticosterone and deoxycorticosterone metabolites. Increased urinary corticosterone metabolites are indicative of CYP11B2 (18-oxidase) inhibition with clinical features reminiscent of patients with inborn corticosterone methyloxidase type II deficiency. An off-target effect on CYP19A1 was not observed as indicated by no clinical changes in testosterone and estradiol levels. Therefore, dexfadrostat exhibits the ideal structural features for binding and catalytic inhibition of CYP11B2 but not CYP11B1. Clinically, treatment with dexfadrostat phosphate leads to suppression of aldosterone levels by inhibiting predominantly one or both final CYP11B2-mediated reactions.

Lactate Dehydrogenase Inhibitors Suppress Borrelia burgdorferi Growth In Vitro.

Borrelia burgdorferi, the causative agent of Lyme disease, has a highly reduced genome and relies heavily on glycolysis for carbon metabolism. As such, established inhibitors of lactate dehydrogenase (LDH) were evaluated in cultures to determine the extent of their impacts on B. burgdorferi growth. Both racemic and enantiopure (AT-101) gossypol, as well as oxamate, galloflavin, and stiripentol, caused the dose-dependent suppression of B. burgdorferi growth in vitro. Racemic gossypol and AT-101 were shown to fully inhibit spirochetal growth at concentrations of 70.5 and 187.5 μM, respectively. Differences between racemic gossypol and AT-101 efficacy may indicate that the dextrorotatory enantiomer of gossypol is a more effective inhibitor of B. burgdorferi growth than the levorotatory enantiomer. As a whole, LDH inhibition appears to be a promising mechanism for suppressing Borrelia growth, particularly with bulky LDH inhibitors like gossypol.

The Activity of Some Antibiotics Depend on Stereochemistry of Them (Its Structure)

The chiral carbon in biological compounds lead to its activity, for example, the beta lactam ring contains two carbon centers carbon number three and carbon number four both are chiral carbon. This chirality plays important role in the activity and bind with structures activity relationship. Also the ofloxacin act on topoisomerase which required for protein Synthesis of microorganism, the ofloxacin when become Levo isomer not only racemic mixture the activity is more than the racemic or Dextro isomer. Also, the old Antibiotics Chloramphenicol the RR’ isomers only active not the other isomers of Chloramphenicol.

Effect of Isobaric Levobupivacaine and Fentanyl versus Isobaric Ropivacaine and Fentanyl as an Adjuvant in Patients Undergoing Transurethral Resection of the Prostate: A Randomised Clinical Study

Introduction: Ropivacaine is a newer local anaesthetic proven to have a lower systemic toxicity profile, particularly in terms of cardiac and Central Nervous System (CNS) toxicity, than the racemic and levorotatory isomers of bupivacaine, especially in elderly patients. Fentanyl, as an adjuvant, enhances analgesia and promotes early postoperative mobility. Aim: To assess and compare the efficacy and safety of isobaric levobupivacaine and fentanyl versus isobaric ropivacaine and fentanyl in patients undergoing Transurethral Resection of the Prostate (TURP) under Spinal Anaesthesia (SA). Materials and Methods: A randomised clinical study was conducted in the Department of Anaesthesia at SMS Medical College and Attached Hospitals, Jaipur, Rajasthan, India, from March 2021 to January 2023. A total of 60 patients ranging in age from 40 to 80 years, scheduled for elective TURP, were enrolled in the present study. The selected patients were randomly assigned into two groups, each consisting of 30 patients. Group A received a dosage of 2.6 cc of 0.75% isobaric ropivacaine (equivalent to 19.5 mg) along with 0.4 cc of fentanyl (equivalent to 20 micrograms). In contrast, group B received a dosage of 2.6 cc of 0.5% isobaric levobupivacaine (equivalent to 13 mg) and 0.4 cc of fentanyl (20 micrograms). The primary outcome measures were the onset of action, duration of sensory-motor block, and postoperative analgesia. Data were analysed using Epi Info version 7.2.1.0 statistical software. The quantitative data collected were summarised using the mean and Standard Deviation (SD). A p-value of less than or equal to 0.05 was considered statistically significant. Results: The majority of patients in the present study were elderly males in both groups. The mean age distribution in group A was 64.27±8.17, and in group B, it was 65.13±7.1. Both groups were comparable and not statistically significant (p=0.634). The mean weight of the two groups was similar, with group A at 64.9±7.49 kg and group B at 63.1±6.96 kg. Both groups were comparable and not statistically significant (p=0.334). The mean height of the patients was 165±4.85 cm in group A and 164±3.83 cm in group B, and it was comparable between the two groups without statistical significance (p=0.145). The duration of sensory block was 241.03±18.88 minutes in group A and 181.5±33.42 minutes in group B. The duration of motor block was 210.7±17.93 minutes in group A and 160±14.82 minutes in group B. Group A demonstrated a significant prolongation of sensory (p<0.001) and motor (p<0.001) block, as well as postoperative analgesia, when compared to 0.5% levobupivacaine with fentanyl. Conclusion: The requirement for rescue analgesia occurred earlier in the levobupivacaine group. Therefore, the use of ropivacaine with fentanyl for spinal anaesthesia in TURP cases is a superior alternative compared to levobupivacaine with fentanyl, as it provides satisfactory quality and duration of block, as well as a longer duration of postoperative analgesia, as assessed by the Visual Analogue Scale (VAS) score and Modified Bromage score.

Chemoenzymatic Synthesis of Optically Active Ethereal Analog of iso-Moramide-A Novel Potentially Powerful Analgesic †.

To develop potent and safer analgesics, we designed and synthesized a novel enantiomerically enriched ethereal analog of (R)-iso-moramide, namely 2-[(2R)-2-(morpholin-4-yl)propoxy]-2,2-diphenyl-1-(pyrrolidin-1-yl)ethan-1-one. The titled active agent can potentially serve as a powerful synthetic opiate with an improved affinity and selectivity toward opioid receptors (ORs). This hypothesis was postulated based on docking studies regarding the respective complexes between the designed ligand and µ-OR, δ-OR, and κ-OR. The key step of the elaborated asymmetric synthesis of novel analog involves lipase-catalyzed kinetic resolution of racemic 1-(morpholin-4-yl)propan-2-ol, which was accomplished on a 10 g scale via an enantioselective transesterification employing vinyl acetate as an irreversible acyl donor in tert-butyl methyl ether (MTBE) as the co-solvent. Next, the obtained homochiral (S)-(+)-morpholino-alcohol (>99% ee) was functionalized into corresponding chloro-derivative using thionyl chloride (SOCl2) or the Appel reaction conditions. Further transformation with N-diphenylacetyl-1-pyrrolidine under phase-transfer catalysis (PTC) conditions using O2-saturated DMSO/NaOH mixture as an oxidant furnished the desired levorotatory isomer of the title product isolated in 26% total yield after three steps, and with 89% ee. The absolute configuration of the key-intermediate of (R)-(–)-iso-moramide was determined using a modified form of Mosher’s methodology. The preparation of the optically active dextrorotatory isomer of the titled product (87% ee) was carried out essentially by the same route, utilizing (R)-(–)-1-(morpholin-4-yl)propan-2-ol (98% ee) as a key intermediate. The spectroscopic characterization of the ethereal analog of iso-moramide and the enantioselective retention relationship of its enantiomers using HPLC on the cellulose-based chiral stationary phase were performed. Moreover, as a proof-of-principle, single-crystal X-ray diffraction (XRD) analysis of the synthesized 2-[(2R)-2-(morpholin-4-yl)propoxy]-2,2-diphenyl-1-(pyrrolidin-1-yl)ethan-1-one is reported.

Noradrenergic modulation of Dex-ketoprofen analgesia in preclinical orofacial pain

Dexketoprofen (DEX) is the dextrorotatory enantiomer of S (+) configuration with a high antinociceptive activity of ketoprofen. The aim of this study was to evaluate the pharmacological interaction of DEX with the noradrenergic antagonist's prazosin, yohimbine, propranolol and atenolol in the formalin orofacial pain in mice. Analgesia to nociceptive and inflammatory pain was evaluated by dose response curves to DEX before and after the i.p. administration of 1.0 mg/kg of prazosin, or yohimbine, or propranolol or atenolol. Results are presented as means ± SEM and differences were calculated by one-way ANOVA, followed by Tukey’s post-test. DEX produced a dose-related antinociceptive effect with varying potencies in both trial phases, with prazosin and yohimbine increasing the efficacy of DEX and propranolol and atenolol having no effect. These findings suggests that the increased efficacy of DEX cannot be explained by only inhibition of COXs, since it may be a consequence of multiple pharmacodynamic interactions induced by the activation of a-adrenoceptors in the opioidergic, cannabinoid, nitrergic or serotonergic mechanisms involved in pain. These results indicate that the combination of DEX with prazosin or yohimbine could be a new and effective alternative for the management of pain.

Entactogens: How the Name for a Novel Class of Psychoactive Agents Originated.

At first glance, it appears there is little difference between the molecular structures of methylenedioxymethamphetamine (MDMA), which has an N-methyl attached to its amino group, and methylenedioxyamphetamine (MDA), a primary amine that is recognized to have hallucinogenic activity. It is known from studies with other hallucinogenic amphetamines that N-methylation of hallucinogenic amphetamines attenuates or abolishes hallucinogenic activity. Nevertheless, MDMA is biologically active and has a potency only slightly less than its MDA parent. Importantly, it is the Ievo-isomer of hallucinogenic phenethylamines that is more biologically active, whereas it is the dextro isomer of MDMA that is more active. This reversal of stereochemistry for the activity of two very closely related molecules is a very powerful clue that their mechanisms of action differ. Finally, extension of the alpha-methyl of hallucinogenic amphetamines to an alpha-ethyl moiety completely abolishes their hallucinogenic activity. Ultimately, we extended the alpha-methyl group of MDMA to an alpha-ethyl to afford a molecule we named (N-Methyl-1-(1,3-benzodioxol-5-yl)-2-butanamine (MBDB) that retained significant MDMA-like psychoactivity. Hence, there are three structural features that distinguish MDMA from the hallucinogenic amphetamines: (1) the N-methyl on the basic nitrogen, (2) the reversal of stereochemistry and, (3) tolerance of an alpha-ethyl moiety as contrasted with the alpha-methyl of hallucinogenic phenethylamines. Clearly, MDMA is distinct from classical hallucinogenic phenethylamines in its structure, and its psychopharmacology is also unique. Thus, in 1986 I proposed the name “Entactogen” for the pharmacological class of drugs that includes 3,4-methylenedioxymethamphetamine (MDMA) and other substances with a similar psychopharmacological effect. The name is derived from roots that indicate that entactogens produce a “touching within.” Rather than having significant psychostimulant, or hallucinogenic effects, MDMA powerfully promotes affiliative social behavior, has acute anxiolytic effects, and can lead to profound states of introspection and personal reflection. Its mechanism of action is now established as involving transport of MDMA by the neuronal serotonin reuptake carrier followed by carrier-mediated release of stored neuronal serotonin.

Sulpiride-induced hyperprolactinaemia increases retinal vasoinhibin and protects against diabetic retinopathy in rats.

Excessive vasopermeability and angiogenesis compromise vision in diabetic macular oedema (DME) and diabetic retinopathy (DR). Vasoinhibin is a fragment of the hormone prolactin (PRL) that inhibits diabetes-induced retinal hypervasopermeability and ischaemia-induced retinal angiogenesis in rodents. Hyperprolactinaemia generated by the dopamine D2 receptor antagonist, levosulpiride, is associated with higher levels of vasoinhibin in the vitreous of patients with DR, implying a beneficial outcome due to vasoinhibin-mediated inhibition of retinal vascular alterations. Here, we tested whether hyperprolactinaemia induced by racemic sulpiride increases intraocular vasoinhibin levels and inhibits retinal hypervasopermeability in diabetic rats. Diabetes was generated with streptozotocin and, 4weeks later, rats were treated for 2weeks with sulpiride or osmotic minipumps delivering PRL. ELISA, Western blot, and Evans blue assay were used to evaluate serum PRL, retinal vasoinhibin, and retinal vasopermeability, respectively. Hyperprolactinaemia in response to sulpiride or exogenous PRL was associated with increased levels of vasoinhibin in the retina and reduced retinal hypervasopermeability. Furthermore, sulpiride decreased retinal haemorrhages in response to the intravitreal administration of vascular endothelial growth factor (VEGF). Neither sulpiride nor exogenous PRL modified blood glucose levels or bodyweight. We conclude that sulpiride-induced hyperprolactinaemia inhibits the diabetes- and VEGF-mediated increase in retinal vasopermeability by promoting the intraocular conversion of endogenous PRL to vasoinhibin. These findings support the therapeutic potential of sulpiride and its levorotatory enantiomer, levosulpiride, against DME and DR.

Structurally diverse biflavonoids from Dysosma versipellis and their bioactivity.

Five pairs of new biflavonoid enantiomers, (±)-dysosmabiflavonoids A-E (1-5), two new biflavonoids, dysosmabiflavonoids F-G (6-7), and four biosynthetically related precursors (8-11) were isolated from the roots and rhizomes of Dysosma versipellis. Their structures were elucidated by extensive spectroscopic analysis, including HR-ESI-MS and 2D NMR. Their absolute configurations were determined by comparison of the calculated and experimental ECD spectra. All isolated compounds were evaluated for AChE inhibitory activity. Compounds 6 and 7 exhibited more potent inhibitory activities with IC50 values of 1.42 and 0.73 µM, respectively, than their biosynthetically related precursors kaempferol (8, 17.90 µM) and quercetin (9, 3.96 µM). The preliminary structure-activity relationship study indicated that the connection mode of biflavonoid subunits, oxidation degree of the C ring, and 3,4-dihydroxy group of the B ring were important structural factors for AChE inhibitory activity. Racemates 1-5 and their corresponding levorotatory and dextrorotatory enantiomers were tested for their potential to impede the generation of NO in lipopolysaccharide-stimulated RAW264.7 cells, and their mushroom tyrosinase inhibitory effect. Racemate 1 displayed more potent mushroom tyrosinase inhibitory activity (IC50, 28.27 µM) than the positive control kojic acid (IC50, 32.59 µM). D. versipellis may have therapeutic potential for melanogenesis disorders and neurodegenerative diseases.

Phytochemical investigation of extracts of rhizomes of Hedychium Spicatum Sm. in A. Rees of Himachal Pradesh, India

Hedychium Spicatum is a rhizomatous perennial plant of various ethnomedicinal significance, which belongs to Zingiberaceae family.In the present study, H.Spicatum extracts were investigated for the presence of major phytochemical compounds. The dried and powdered rhizomes were extracted employing Soxhlet extraction with selective solvents of varying polarities viz water, ethanol, petroleum ether and diethyl ether. Qualitative phytochemical analysis of each of these extracts of H.Spicatum suggested the existence of flavonoids, phenolic compounds, carotenoids, alkaloids, reducing sugars (carbohydrate), proteins, steroids, saponins and oils. Greater extent of unsaturation was observed in diethyl ether and petroleum ether extracts. These extracts were also examined for their physico-chemical properties. All of the studied extracts were found to be optically active, specifically dextro rotatory. The phytochemicals present in the rhizomes suggest potential ethnomedicinal application of the species in the treatment, control and management of diseases and for new drug discovery.

FinDr: A web server for in silico D-peptide ligand identification

In the rapidly expanding field of peptide therapeutics, the short in vivo half-life of peptides represents a considerable limitation for drug action. D-peptides, consisting entirely of the dextrorotatory enantiomers of naturally occurring levorotatory amino acids (AAs), do not suffer from these shortcomings as they are intrinsically resistant to proteolytic degradation, resulting in a favourable pharmacokinetic profile. To experimentally identify D-peptide binders to interesting therapeutic targets, so-called mirror-image phage display is typically performed, whereby the target is synthesized in D-form and L-peptide binders are screened as in conventional phage display. This technique is extremely powerful, but it requires the synthesis of the target in D-form, which is challenging for large proteins. Here we present finDr, a novel web server for the computational identification and optimization of D-peptide ligands to any protein structure (https://findr.biologie.uni-freiburg.de/). finDr performs molecular docking to virtually screen a library of helical 12-mer peptides extracted from the RCSB Protein Data Bank (PDB) for their ability to bind to the target. In a separate, heuristic approach to search the chemical space of 12-mer peptides, finDr executes a customizable evolutionary algorithm (EA) for the de novo identification or optimization of D-peptide ligands. As a proof of principle, we demonstrate the validity of our approach to predict optimal binders to the pharmacologically relevant target phenol soluble modulin alpha 3 (PSMα3), a toxin of methicillin-resistant Staphylococcus aureus (MRSA). We validate the predictions using in vitro binding assays, supporting the success of this approach. Compared to conventional methods, finDr provides a low cost and easy-to-use alternative for the identification of D-peptide ligands against protein targets of choice without size limitation. We believe finDr will facilitate D-peptide discovery with implications in biotechnology and biomedicine.

A prospective randomized clinical study to compare the efficacy of 0.25% bupivacaine with clonidine and 0.25% levobupivacaine with clonidine in supraclavicular brachial plexus block for upper limb surgeries

:Bupivacaine is an amide local anesthetic, available as a racemic mixture of Dextro and Levorotatory Isomers. Due to its rapid onset and longer duration of anesthesia, It is routinely preferred in various regional anesthetic techniques. However, it is associated with serious cardiovascular and neurological toxicity. Its pure S- enantiomer, Levobupivacaine having similar pharmacological profile is known to have lesser cardiovascular and CNS toxicity. Combining adjuvants like clonidine, a centrally acting partial alpha-2-adrenergic agonist to improve quality of anesthesia is common practice. Hence, the aim of our study is to compare efficacy and safety of 0.25% Levobupivacaine and 0.25% Bupivacaine when combined with clonidine in supraclavicular brachial plexus block for upper limb surgeries.Eighty patients aged between 18 to 60 years with ASA physical status I-II, scheduled for elective upper limb surgeries under were randomized into two groups. Peripheral nerve stimulator guided Supraclavicular brachial plexus block was administered. Group BC received 30ml of 0.25% Bupivacaine plus 1µg/kg Clonidine and Group LC 30ml of 0.25% Levobupivacaine plus 1µg/kg Clonidine. The time of onset of sensory and motor block, duration of sensory and motor block, perioperative hemodynamic parameters, postoperative pain for 24hours and adverse effects were studies.Group LC had faster onset of sensory block (p= 0.014) as well as faster onset of motor block (p= 0.012) compared to group BC. However, durations of sensory block and motor block were statistically not significant in both the groups (p>0.05). Perioperative hemodynamic parameters and assessment of pain during 24 hours of post operative period were comparable and statistically not significant.1mcg/kg of clonidine used as an adjuvant to 30ml of 0.25% Levobupivacaine produces faster onset of sensory and motor block compared to 0.25% Bupivacaine in supraclavicular brachial plexus block. However, similar anesthetic efficacy in terms of duration of sensory and motor block, hemodynamics and postoperative analgesia were observed.

Discrimination of Pharmaceutical Tablets Based on the Analysis of Solid-State Structures of Ingredients Using Terahertz Transmission Spectroscopy with the Injection-Seeded Parametric Generation Technique.

A frequency-domain terahertz (THz) spectrometer that uses a tunable source, called an injection-seeded THz parametric generator, was applied to the analysis of solid-state structures of ingredients in pharmaceutical tablets, and its performance on discriminating pharmaceutical products was evaluated. The spectrometer has a dynamic range of 70 dB at 2 THz and is suitable for analyzing materials such as pharmaceutical ingredients that often have characteristic absorption peaks between 0.5 and 2.5 THz. Nine ofloxacin (racemate) and four levofloxacin (levorotatory enantiomer) tablet products commercially available in Japan were used as samples. They contain 8–12 additives in addition to the API. The sample tablets were filed down to a thickness of 1.2 mm (ofloxacin tablets) and 1.6 mm (levofloxacin tablets) to obtain transmission spectra over the wide spectral range of 0.8–2.1 THz. The absorption spectra obtained from the spectrometer were preprocessed by the second derivative; then, principal component analysis (PCA) was conducted on the results. Next, quadratic discriminant analysis (DA) was conducted on the scores of the three PCA components. The accuracy of the DA for all 13 products was 96.1%. In addition to the difference in crystal forms of the active ingredient, the small differences in the formulation were clearly discriminated using the THz absorption spectra. The spectrometer combined with data analysis shows potential for applications such as identifying pharmaceutical tablets, monitoring the stability of production processes, evaluating the stability of formulations during storage, and detecting counterfeit drugs on the market.

Design and discovery of a high affinity, selective and β-arrestin biased 5-HT7 Receptor Agonist.

Compound 1c, 5-chloro-2-(2-(3,4-dihydroisoquinolin-2(1H)-yl)ethyl)-2,3-dihydro-1H-inden-1-one was previously reported from our laboratory showing high affinity binding to the 5-HT7 receptor (Ki = 0.5 nM). However, compound 1c racemizes readily upon enantiomeric separation. To prevent racemization, we have redesigned and synthesized methyl and carboxyethyl analogs, compounds 2 and 3 respectively, whose binding affinities were similar to those of compound 1c. Compounds 2 and 3 cannot undergo racemization since tautomerism was no longer possible and thus, compound 2 was selected for enantiomeric separation and further evaluation. Upon enantiomeric separation, the levorotatory enantiomer, (-)2 or 2a demonstrated a higher affinity (Ki = 1.2 nM) than the (+)2 or 2b enantiomer (Ki = 93 nM) and a β-arrestin biased functional selectivity for the 5-HT7 receptor. Although 2a showed about 8 times less activity than 5-HT in the Gs pathway, it showed over 31 times higher activity than 5-HT in the β-arrestin pathway. This constitutes a significant β-arrestin pathway preference and shows 2a to be more potent and more efficacious than the recently published β-arrestin biased 3-(4-chlorophenyl)-1,4,5,6,7,8-hexahydropyrazolo[3,4-d]azepine, the N-debenzylated analog of JNJ18038683 (Compound 7).

What Is the Most Important and Impactful Paper Related to Movement Disorder Therapy Published in the 20th Century?

What Is the Most Important and Impactful Paper Related to Movement Disorder Therapy Published in the 20th Century?

Principles of personalized medicine and modern pharmaceutical technologies to optimize levodopa therapy of Parkinson's disease

Levodopa (3-hydroxy-L-tyrosine, the levorotatory isomer of 3,4-dihydroxyphenylalanine) is a biological precursor of the neurotransmitter dopamine and has been the gold standard in the treatment of Parkinson’s disease for over 50 years. The widespread use of levodopa in clinical practice has not only provided neurologists with unique data from many years of symptomatic replacement therapy for a severe neurodegenerative disease but has also clearly identified several serious problems associated with levodopa absorption and metabolism. This article discusses the modern approaches to personalized medicine, which aim to overcome the numerous difficulties in managing patients with Parkinson’s disease and long-term levodopa use. A major focus is the review of strategies for selecting the optimal levodopa dosage regimen in specific patients and the main innovative dosage forms of this drug that improve its pharmacokinetics. For citation: Abaimov D.A., Fedotova E.Yu., Poleshchuk V.V., Andreev M.N., Trifonova O.P., Lokhov P.G., Illarioshkin S.N. [Principles of personalized medicine and modern pharmaceutical technologies to optimize levodopa therapy of Parkinson's disease]. Annals of clinical and experimental neurology 2021; 15(2): 73–82. (In Russ.) DOI: http://dx.doi.org/10.25692/ACEN.2021.2.9

Reinforcing and Stimulant-Like Effects of Methamphetamine Isomers in Rhesus Macaques.

Monoamine releasers such as d-methamphetamine (d-MA) can reduce cocaine use in laboratory studies and have been forwarded for the management of cocaine use disorder (CUD). However, the proven abuse liability of d-MA has limited enthusiasm for clinical use. The levorotatory isomer of MA, l-MA, appears to have lesser stimulant effects, possibly due to its preferential norepinephrine-releasing properties compared with dopamine. The present study evaluated the abuse potential of l-MA by comparing its reinforcing effects with known stimulant drugs of abuse in nonhuman primates. Adult rhesus macaques (N = 4) responded for intravenous injections of cocaine, d-MA, methcathinone (MCAT), or l-MA under a fixed-ratio (FR) schedule of reinforcement; reinforcing effectiveness was evaluated using behavioral economic demand procedures. In a separate cohort (N = 9), daily activity and food-reinforced responding were assessed during 100 days of treatment with daily dosages of l-MA (2.3 mg/kg per day, i.v.) or d-MA (0.74 mg/kg per day, i.v.) previously shown to decrease cocaine self-administration. Results show that all drugs maintained self-administration, with peak injections reaching ∼100 inj per session for cocaine, MCAT, and d-MA and ∼50 inj per session for l-MA . In demand studies, self-administration of each drug gradually decreased as FR size increased. The exponential model of demand indicated that the reinforcing effectiveness of l-MA was significantly less than the other drugs studied. Chronic l-MA treatment did not appreciably alter daily activity and only transiently suppressed food-reinforced responding. These data, coupled with previous findings that l-MA effectively reduces stimulant self-administration, suggest that l-MA, or other norepinephrine-preferring releasers, may serve as agonist medication for CUD with lesser abuse liability than common psychostimulants. SIGNIFICANCE STATEMENT: Development of pharmacotherapies for cocaine use disorder remains a formidable challenge. Agonist-based therapies show promise, but enthusiasm is tempered by the abuse liability of previously proposed medications. This study evaluated the abuse liability and chronic treatment effects of methamphetamine's levorotatory isomer (l-MA). l-MA demonstrated lower abuse liability compared with commonly abused stimulants and produced few untoward effects. In the context of recent studies demonstrating that l-MA attenuates stimulant self-administration, these findings support l-MA's potential as a pharmacotherapy for stimulant addiction.

A rational pharmacotherapeutic study of the prevalent prescription patterns of delamanid, ofloxacin, levofloxacin, and bedaquiline among the multi-drug resistant tuberculosis patients in global multi-centre tertiary care hospitals

Background: Delamanid, a nitro-dihydro-imidazooxazole, is a bactericidal cell wall methoxy-mycolic and keto-mycolic acids biosynthesis inhibitor in actively replicating, dormant, and intracellular tuberculosis, and both drug-susceptible and drug-resistant strains of M. tuberculosis and M. kansasii, decreasing hydrophobicity and facilitating better bacterial drug penetration. Delamanid promotes intracellular generation of microbiocidal nitrogen oxidative intermediaries including nitric oxide, toxic even to dormant M. tuberculosis. Ofloxacin, the racemic mixture and levofloxacin, the S-or levorotatory isomer of ofloxacin, are bactericidal to M. tuberculosis, MAC, M. fortuitum, and other atypical mycobacteria, with inhibitory effect on DNA gyrase, DNA topoisomerase IV and IL-1α, IL-6, IL-8. Bedaquiline, a novel diarylquinoline, inhibits mycobacterial adenosine triphosphate synthase of M. tuberculosis, disrupting mycobacterial energy metabolism and replication. Bedaquiline’s initial bacteriostatic action is followed by a bactericidal effect after 5-7 days. The objective was to perform a rational pharmacotherapeutic study of the prevalent prescription patterns of delamanid, ofloxacin, levofloxacin, and bedaquiline, among the multi-drug resistant tuberculosis patients, in global multi-centre tertiary care hospitals.Methods: A multi-centre, retrospective, observational and analytical study of clinical prescriptions of 100 multi-drug resistant tuberculosis patients in hospitals, were performed. For 24-48 weeks, these patients had been prescribed anti-tubercular drugs, like delamanid 100 mg and ofloxacin 400 mg twice daily, levofloxacin 750 mg and bedaquiline 400 mg once daily followed by 200 mg thrice weekly, as part of MDR-TB treatment regimens. The no. of prescriptions for each drug were recorded, and the corresponding prescription rates were statistically derived in percentages. Results: Delamanid was most commonly prescribed (32 prescriptions, 32%), followed by ofloxacin (29 prescriptions, 29%), levofloxacin (24 prescriptions, 24%), and bedaquiline (15 prescriptions, 15%). The completeness of the prescription contents, the dose of drug, the duration of treatment, the instructions of medication, the frequency of drug intake, the name of the drug and the dosage form of the drug were observed in 100% of prescriptions.Conclusions: Prescription frequency of delamanid was followed by ofloxacin, levofloxacin and bedaquiline. Prescription content analyses showed 100% completeness.

Optimizing Chiral Selectivity in Practical Life-Detection Instruments.

Preferential uptake of either levorotatory (L) or dextrorotatory (D) enantiomer of a chiral molecule is a potential planetary life-detection method. On Earth, bacteria, as a rule, metabolize D-sugars and L-amino acids. Here, we use growth experiments to identify exceptions to the rule and their potential impact on the method's reliability. Our experiments involve six strains of Bacillus and collective uptake of the sugars glucose and arabinose, and the amino acids alanine, glutamic acid, leucine, cysteine, and serine-all of which are highly soluble. We find that selective uptake is not evident unless (1) each sugar is tested individually and (2) multiple amino acids are tested together in a mixture. Combining sugars should be avoided because, as we show in Bacillus bacteria, the same organisms may catabolize one sugar, glucose, in D-form and another sugar, arabinose, in L-form. Single amino acids should be avoided because bacteria can access certain proteinogenically incompatible enantiomers using specific racemases. Specifically, bacteria contain an alanine acid racemase and can catabolize D-alanine if no other D-amino acids are present. The proposed improvements would reliably separate nonselective chemical reactions from biological reactions and, if life is indicated, inform whether the selective patterns for amino acids and sugars are the same as on Earth.